Chronic Alcohol and Brain Stress Circuit Response Alcoholism is a chronic relapsing illness in which alcohol-related neuroadaptations in brain stress and reward pathways are known to promote persistent craving or compulsive alcohol seeking, a hallmark symptom in both the development of alcoholism and in alcohol relapse susceptibility. In the first funding period of this project, we found that chronic alcohol abuse is associated with a series of stress-related alterations that accompany the compulsive alcohol seeking state, and these changes contribute to high relapse susceptibility in alcoholics completing inpatient treatment. Furthermore, preliminary results comparing moderate (MD), moderate bingeing (MB) and heavy (HD) non-dependent drinkers studied in the current period suggested a progressive increase in sensitivity to stress-induced and cue-induced alcohol craving and associated physiological and biochemical alterations associated with heavy drinking and/or binge drinking. These findings suggest that alcohol-related alterations in stress responses and stress and cue-induced craving may contribute to the development of compulsive alcohol seeking. Therefore, in this competing renewal application, we extend and expand the findings from the current period to examine the role of stress in the development of compulsive alcohol seeking and in increased stress and cue-related alcohol consumption in non-dependent heavy and binge drinkers. A 5-year project with a cross-sectional design is proposed that will study demographically-matched samples of 50 MD, 50 MB and 50 HD drinkers, to address the following specific aims: (1) To examine whether exposure to stress and to alcohol cues increases alcohol craving, negative emotions, behavioral distress responses and alters physiological and biochemical responses differentially across the three drinking groups. (2) To examine whether exposure to stress and to alcohol cues vs. neutral cues increases alcohol consumption in the alcohol taste test, and if amount consumed vary as a function of drinking group. (3) To examine whether subjective, physiological and biochemical markers of distress and compulsive seeking is predictive of amounts of alcohol consumed in each condition. (4) To examine the influence of demographic and individual differences variables, such as gender, race, family history of alcoholism (FH), co-morbid use of nicotine and poor cognitive/impulse control in stress and cue-related responses and level of alcohol consumption. Addressing these questions will increase an understanding of the mechanisms by which alcohol consumption and stress responses interact to influence development of compulsive alcohol seeking and vulnerability to loss of control drinking, and the results will have significant implications for the development of new prevention and treatment interventions for alcoholism. Alcoholism is among the top three causes of preventable death and disease in the US (Mokdad et al., 2004; Room et al., 2005). Stress plays an important role in the development of alcoholism and in high vulnerability to alcohol relapse. The proposed study will provide a greater understanding of the mechanism by which stress and alcohol consumption interacts to influence development of compulsive alcohol seeking and vulnerability to stress-induced drinking, and the results will have significant implications for the development of new prevention and treatment interventions for alcoholism.